Abstract
Alzheimer's disease (AD), the most common form of dementia, is marked by amyloid plaque (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation, and neuronal degeneration. Despite significant efforts, effective treatment remains lacking. Disrupted communication between neurons and glia plays a key role in AD onset, with microglia-mediated neuroinflammation exacerbating neuronal damage. Extracellular vesicles (EVs) are involved in spreading neuroinflammation and toxic protein aggregates. EVs from neural stem cells (NSC-EVs) show promise in modulating neuroinflammation and enhancing neurogenesis in AD models. This study aims to examine adult neurogenesis and EV characteristics in the 5XFAD model, focusing on miRNA profiles and their potential as therapeutic targets for AD, which may lead to innovative treatments. Results A major achievement of the project was the establishment of a robust and reproducible AD-like neurosphere model to investigate the mechanisms regulating adult neurogenesis under pathological conditions. Adult neurogenesis is increasingly recognized as a process impaired in Alzheimer's disease (AD) and closely associated with the chronic inflammatory environment that characterizes disease progression. By exposing wild-type neurospheres to Aβ1–42, we reproduced key pathological features of AD and demonstrated that Aβ alters neural stem cell behavior by reshaping the balance between proliferation and differentiation. Rather than simply affecting cell growth, Aβ induced a dynamic remodeling of the neurogenic program, suggesting that neural stem cells actively adapt their developmental fate in response to pathological stimuli. Among the molecular changes identified, a panel of cell fate- and inflammation-associated miRNAs, including miR-34a, let-7b, miR-124a, miR-125b, and miR-9, was characterized in both neurospheres and their corresponding extracellular vesicles (EVs). These miRNAs are known to regulate neural stem cell proliferation, neuronal differentiation, lineage commitment, and inflammatory signaling, supporting their potential role in coordinating the response of the adult neurogenic niche to AD-related pathology. Among these candidates, miR-34a emerged as the most consistently dysregulated molecule. Aβ-treated neurospheres displayed a significant increase in miR-34a expression, accompanied by molecular changes consistent with progression toward neuronal differentiation. Given its established role in regulating cell-cycle progression and neuronal maturation, these findings suggest that miR-34a may contribute to the adaptive response of neural stem cells to AD-related pathological conditions. Notably, the same dysregulation was detected in EVs released by Aβ-treated neurospheres, indicating that neural stem cells may package this regulatory signal into EVs and potentially transmit it to neighboring cells within the neurogenic niche. The project also demonstrated that Aβ profoundly influences EV biology. Although the overall size distribution of EVs remained unchanged, Aβ selectively increased the release of small EVs, suggesting that pathological conditions affect not only EV cargo but also the dynamics of EV-mediated intercellular communication. The enrichment of miR-34a within these vesicles further supports the concept that EVs are active mediators of biological signaling rather than passive carriers of disease-associated molecules. Importantly, the identification of miR-34a in both neural stem cells and their EVs, together with independent functional evidence demonstrating its role in regulating microglial homeostasis, supports the hypothesis that this miRNA represents a molecular link between impaired adult neurogenesis and neuroinflammation. Overall, the project provides new mechanistic insights into the interplay between adult neurogenesis, extracellular vesicle biology, and neuroinflammation in Alzheimer's disease. Beyond the scientific findings, it established validated experimental platforms and optimized methodologies that will support future studies aimed at identifying EV-associated biomarkers and developing innovative therapeutic strategies targeting neuron–glia communication in neurodegenerative disorders.
Dettagli del progetto
Responsabile scientifico: Francesca Massenzio
Strutture Unibo coinvolte:
Dipartimento di Farmacia e Biotecnologie
Coordinatore:
Università degli studi di Modena e Reggio Emilia - UNIMORE(Italy)
Contributo totale Unibo: Euro (EUR) 93.894,00
Durata del progetto in mesi: 24
Data di inizio
18/10/2023
Data di fine:
28/02/2026
